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The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction (RAZE)

Primary Purpose

Heart Failure With Preserved Ejection Fraction

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Ranolazine
Placebo
Sponsored by
University of California, San Diego
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure With Preserved Ejection Fraction focused on measuring HFPEF, Heart Failure, HF w/ preserved EF, Preserved EF, Preserved Ejection Fraction, Diastolic Dysfunction

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

I. Inclusion Criteria

  • Age > 18 years old

  • Diagnosis of Heart Failure (HF) with Preserved Ejection Fraction (PEF)

    • Signs or symptoms of heart failure (breathlessness, pulmonary congestion, edema, fatigue), NYHA (New York Heart Association) Class II-III HF AND
    • LVEF (Left Ventricular Ejection Fraction) > 45% AND

    • Evidence of elevated LV filling pressures

      1. E/e-prime (E/e') mitral ratio > 8. Mitral E/e' ratio has been proposed as a noninvasive measure of left ventricular filling pressure.
      2. Brain natiuretic peptide (BNP) > 80 pg/mL. BNP is biomarker of ventricular wall stress.
  • Pulmonary Artery systolic pressure estimated at > 35 mm Hg on echocardiography
  • Stable medical management for at least 1 month

II. Exclusion Criteria

  • Inability to perform 6 minute walk (6MW) test or 6 minute walk distance > 550 meters at baseline
  • Inability to perform the Naughton protocol exercise test, or an absolute contraindication to exercise testing
  • Decompensated heart failure
  • Clinically significant valvular disease or congenital cardiac defects
  • Clinical diagnosis of Chronic obstructive pulmonary disease (COPD) or significant lung pathology
  • Prior treatment with ranolazine
  • Percutaneous coronary intervention within the past 6 months or planned intervention during the study period
  • Acute coronary syndrome within the prior 2 months
  • Presence of uncorrected perfusion defects on stress testing
  • Presence of angina
  • Any rhythm other than sinus
  • Electrocardiogram measured QTc interval > 500 msec
  • Clinically significant hepatic impairment (ALT/AST > 3x upper limit of normal)
  • Participation in another investigational drug or device study within 1 month prior to screening
  • Females of childbearing potential
  • Current treatment with potent inhibitors of hepatic cytochrome P450 (CYP) enzyme complex pathways affecting drug metabolism (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)
  • Current treatment with CYP3A and/or P-Glycoprotein (Pgp) inducers (e.g. rifampin, rifampicin, carbamazepine, St. John's wort)
  • Any other conditions that in the opinion of the investigators are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study.

Sites / Locations

  • University of California, San Diego

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Ranolazine

Placebo

Arm Description

Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)

Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)

Outcomes

Primary Outcome Measures

Change in Exercise Capacity at 6 Weeks
Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks.
Change in Oxygen Consumption (VO2) at 6 Weeks
Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo.

Secondary Outcome Measures

Change in Quality of Life (QOL) Score
The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points.
Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e')
Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. The percent change is reported.

Full Information

First Posted
December 8, 2011
Last Updated
January 9, 2020
Sponsor
University of California, San Diego
Collaborators
Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT01505179
Brief Title
The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction
Acronym
RAZE
Official Title
The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego
Collaborators
Gilead Sciences

4. Oversight

5. Study Description

Brief Summary
The purpose of this study is to determine whether treatment with Ranolazine will improve exercise capacity in patients with Heart Failure with preserved left ventricular ejection fraction, or HFPEF.
Detailed Description
Denise Barnard, M.D., and her associates, are conducting a research study to find out more about ways to improve symptoms in patients with Heart Failure with Preserved Ejection Fraction (HFPEF). Heart failure with preserved ejection fraction is a condition where the heart squeezes well but is stiff. This stiffness in the heart muscle makes the heart unable to fill, leading to shortness of breath and decreased exercise tolerance. Subjects with HFPEF are asked to participate in this study. There will be approximately 40 participants enrolled in this study. The purpose of this study is to investigate the effects of Ranolazine (Ranexa) in patients with HFPEF. The study is sponsored by the manufacturers of the drug, Gilead Pharmaceuticals. Ranolazine is a drug that affects the ion channels in the heart. In patients with heart failure, these ion channels do not work properly, and contribute to make the heart stiff. A stiff heart leads to the symptoms of shortness of breath which patients with HFPEF experience. Due to its properties, Ranolazine may improve this stiffness. Ranolazine could improve subject's shortness of breath and ability to exercise. Currently, ranolazine carries FDA approval for the treatment of chronic angina only. We intend to study ranolazine in patients with HFPEF, in the absence of documented ischemia, to determine whether the drug's lusitropic properties can improve exercise capacity in HFPEF patients. Previous trials of ranolazine in patients with chronic angina found that there was a dose-dependent relationship between improvements in exercise capacity and ranolazine. However, there did appear to be a plateau in which 1500 mg of ranolazine twice daily improved exercise capacity only slightly more than 1000 mg of ranolazine given twice daily. Additionally, there was a substantially higher rate of adverse events (mainly nausea, dizziness, and asthenia) with the higher dose. Given the desire to maximize benefit and minimize the risk of adverse events, ranolazine 1000 mg by mouth twice daily was chosen as the target dose. To properly evaluate the effects of Ranolazine, this research study is set up as a double blind, placebo controlled study. Subjects will be randomly assigned (like rolling a dice) to either Ranolazine or placebo (inactive substance). Subjects will have a 50% chance of getting the study drug and 50% chance of getting placebo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure With Preserved Ejection Fraction
Keywords
HFPEF, Heart Failure, HF w/ preserved EF, Preserved EF, Preserved Ejection Fraction, Diastolic Dysfunction

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ranolazine
Arm Type
Active Comparator
Arm Description
Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Intervention Type
Drug
Intervention Name(s)
Ranolazine
Other Intervention Name(s)
Ranexa
Intervention Description
Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Primary Outcome Measure Information:
Title
Change in Exercise Capacity at 6 Weeks
Description
Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks.
Time Frame
6 weeks
Title
Change in Oxygen Consumption (VO2) at 6 Weeks
Description
Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo.
Time Frame
6 weeks
Secondary Outcome Measure Information:
Title
Change in Quality of Life (QOL) Score
Description
The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points.
Time Frame
6 weeks
Title
Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e')
Description
Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. The percent change is reported.
Time Frame
6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
I. Inclusion Criteria Age > 18 years old Diagnosis of Heart Failure (HF) with Preserved Ejection Fraction (PEF) Signs or symptoms of heart failure (breathlessness, pulmonary congestion, edema, fatigue), NYHA (New York Heart Association) Class II-III HF AND LVEF (Left Ventricular Ejection Fraction) > 45% AND Evidence of elevated LV filling pressures E/e-prime (E/e') mitral ratio > 8. Mitral E/e' ratio has been proposed as a noninvasive measure of left ventricular filling pressure. Brain natiuretic peptide (BNP) > 80 pg/mL. BNP is biomarker of ventricular wall stress. Pulmonary Artery systolic pressure estimated at > 35 mm Hg on echocardiography Stable medical management for at least 1 month II. Exclusion Criteria Inability to perform 6 minute walk (6MW) test or 6 minute walk distance > 550 meters at baseline Inability to perform the Naughton protocol exercise test, or an absolute contraindication to exercise testing Decompensated heart failure Clinically significant valvular disease or congenital cardiac defects Clinical diagnosis of Chronic obstructive pulmonary disease (COPD) or significant lung pathology Prior treatment with ranolazine Percutaneous coronary intervention within the past 6 months or planned intervention during the study period Acute coronary syndrome within the prior 2 months Presence of uncorrected perfusion defects on stress testing Presence of angina Any rhythm other than sinus Electrocardiogram measured QTc interval > 500 msec Clinically significant hepatic impairment (ALT/AST > 3x upper limit of normal) Participation in another investigational drug or device study within 1 month prior to screening Females of childbearing potential Current treatment with potent inhibitors of hepatic cytochrome P450 (CYP) enzyme complex pathways affecting drug metabolism (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir) Current treatment with CYP3A and/or P-Glycoprotein (Pgp) inducers (e.g. rifampin, rifampicin, carbamazepine, St. John's wort) Any other conditions that in the opinion of the investigators are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Denise D Barnard, MD
Organizational Affiliation
University of California, San Diego
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92037
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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The Effects of Ranolazine on Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction

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